Immunologic memory, the induction of a more rapid and dramatically effective immune response following re-exposure to antigen (Ag), is a fundamental but poorly understood process mediated in part by helper T lymphocytes (Th) which regulate immunity primarily by production of lymphokines. While many studies have examined specific activation of Th lines or polyclonal activation of mixed Th populations from normal animals in vitro, I propose a detailed study of the development, recirculation, and function of normal memory Th using Ag-specific responses. I will employ both in vitro and in vivo models which allow the delineation of 4 stages of Th development on the basis of surface phenotype and function: resting naive (Ag-inexperienced) precursors, primary effectors, resting memory cells, and recently activated memory cells (memory effectors). I will investigate the role of lymphokines/cytokines and of different Ag-presenting bell (APC) populations in generating memory Th. I will also examine the recirculation pathways of resting memory Th and memory effector Th; the activation requirements of memory Th versus naive Th; and whether memory Th and primary effector Th arise from distinct precursors. To isolate and evaluate memory Th, I will use as phenotypic criteria surface markers which exhibit altered expression following Ag-activation (such as Pgp-l, CD45RB, and MEL-14), and as functional criteria, Ag-induced lymphokine production, helper activity (B cell isotype produc- tion), and proliferation, as well as the capacity to transfer long-term Ag-specific Th function to adoptive recipients. The use of T cell receptor transgenic mice which express a single alpha/beta receptor specific for a defined peptide of cytochrome C will enable direct comparison of the activation/APC requirements of naive and memory Th. These studies will provide important information on the regulation of Th development and recirculation, and achieve conditions for selective induction/ differentiation of memory Th subsets, identified by secretion of different arrays of lymphokines. My studies will establish in vivo and in vitro models for manipulation of memory Th by administration of exogenous lymphokines, soluble lymphokine receptors, or antibodies that block lymphokine function. The results may suggest approaches for promoting expansion/selection of Ag-specific memory Th. If the regulation of memory were better understood, it might be possible to pro- mote its development and exploit the properties of memory Th (enhanced responsiveness and capacity to migrate to sites of Ag concentration) to enable targeted delivery of individual lymphokines or combinations of lymphokines for the immunotherapeutic resolution of specific tumors.